There is a remarkably high incidence of co-morbidity between post-traumatic stress disorder (PTSD) and alcohol use disorders in the human population. Some evidence suggests that the co-occurrence of PTSD and alcohol use disorders may arise from inherited genetic and biological factors that influence the risk for both diseases. However, the roles of these risk factors in the development of co-morbid disease have not been defined in humans. The broad, long-term objective of this R01 project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This goal will be achieved by examining the relationship between susceptibility toward learned fear/anxiety and innate propensity toward alcohol drinking behavior in mouse lines that have been selectively bred for high (HAP1 and HAP2) or low (LAP1 and LAP2) alcohol preference. Learned fear/anxiety will be measured using fear-potentiated startle (FPS) as an animal model of PTSD. The goal of Specific Aim 1 is to determine if learned fear/anxiety, as measured by FPS, is associated with a genetic propensity toward alcohol drinking and to examine the effects of alcohol on the acquisition and expression of FPS in HAP/LAP lines. The goal of Specific Aim 2 is to test whether acquisition of learned fear/anxiety increases subsequent alcohol drinking behavior and to examine how this phenomenon may depend on a genetic predisposition toward alcohol preference. The goal of Specific Aim 3 is to characterize hypothalamic-pituitary-adrenal (HPA) axis function in response to fear-conditioning in HAP/LAP lines by measuring corticosterone response profiles and to examine the effect of exogenous corticosterone administration on the acquisition of FPS. The results of this R01 project will provide exciting and novel preclinical data on the genetic and biological factors that may influence risk for developing co-morbid PTSD and alcohol use disorders. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce co-morbid PTSD and alcohol use disorders in people who have an increased risk for these co-morbid diseases.In the human population, post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs frequently with alcohol use disorders, termed co-morbidity. The goal of this project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce the incidence of co-morbid PTSD and alcohol use disorders.